CIN treatment: Excisional procedures: Knife, laser or LEEP?

How to minimize damage and optimize outcome

AHMET GÖÇMEN, MD

ŞİŞLİ MEMORIAL HOSPITAL-İSTANBUL

Precancerous cervical lesions are described in three stages; CIN1, 2, and 3

according to the degree of cellular abnormality and extent of epithelial involvement.

The goal of treatment for CIN is to prevent possible progression to invasive

cancer while avoiding over-treatment of lesions that are likely to regress.

CIN1 lesions usually do not require any treatment unless the lesion is persistent beyond two year.

Given the malignant potential of CIN3, there is an international consensus that these

lesions should be treated following diagnosis, except in pregnancy.

Darragh TM, et al. The Lower Anogenital Squamous Terminology

Standardization Project for HPV-Associated Lesions Arch Pathol Lab Med 2012

Partha Basu, et al. Management of cervical premalignant lesions, Current Problems in Cancer 2018

Principles and techniques of treating CIN

In recent years, some important distinctions have been discovered regarding CIN2.

Studies have shown that immunohistochemical staining for p16INK4 / Ki67 may provide a useful biomarker for prediction of progression of CIN2.

CIN2 lesions over expressing p16INK4 are considered as HSIL andneed treatment.

CIN2 lesions not over–expressing p16INK4 are considered as LSIL andcan be followed up.

All CIN2 lesions should be treated where such facilities do not exist.

Principles and techniques of treating CIN

Darragh TM, et al. The Lower Anogenital Squamous Terminology

Standardization Project for HPV-Associated Lesions Arch Pathol Lab Med 2012

Partha Basu, et al. Management of cervical premalignant lesions,

Current Problems in Cancer 2018

Excisional treatment of these lesions is not without risk and is associated with a significantly increased risk in subsequent pregnancies.

The obstetrical morbidity related to the excisional treatment depends ondimensions of the removed cervical tissue.

The risk of premature delivery following excision appears to be significant

in women whose depth of excised cone is greater than 10 mm.

Principles and techniques of treating CIN

Arbyn M, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated withtreatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008

Kyrgiou M, et al. Obstetrics outcomes after conservative treatment for intraepithelial or earlyinvasive cervical lesions: systematic review and meta-analysis. Lancet 2006

Margin status also has a crucial importance, incomplete excision is

related to a substantial risk of high-grade post-treatment disease.

Therefore, excisional treatment should be used only in well-selected

women with a clear indication for invasive treatment.

Colposcopy would allow for the optimization of excisional procedures

both in terms of margins status and excised cone dimensions.

Colposcopy guided excision may lead to significantly smaller cone

specimens without compromising margin status.

Principles and techniques of treating CIN

Carlo A. Liverani, et al. Length but not transverse diameter of the excision specimen for high-grade cervical intraepithelial neoplasia (CIN 2–3) is a predictor of pregnancy outcome. European Journal of Cancer Prevention 2015Hilal Z, et al . Loop electrosurgical excision procedure with or without intraoperative colposcopy: a randomized trial Am J Obstet Gynecol 2018

• Cold knife conization

• Laser

• Electrosurgery

Loop Electrosurgical Excision Procedure (LEEP) or

Large Loop Excision of Transformation Zone (LLETZ)

Needle Excision of Transformation Zone (NETZ)

Exicisional techniques of treating CIN

Treatment of CIN requires excision of the entire transformation zone rather than only of the visible abnormality.

Type I TZ excision : Central cone length must be 8 mm and not more than 10 mm, 5 mm peripheral cone length of the transformation zone may be sufficient.

Type 2 TZ excision : not more than 15 mm length of tissue excised (10-15 mm)

Type 3 TZ excisions : > 15 mm length (15-20 mm).

Should be used for women with:suspected invasive diseaseproven or suspected glandular diseaseType 3 TZ with proven or suspectedhigh-grade disease.

Bornstein J, et al. 2011 colposcopic terminology of the

International Federation for Cervical Pathology and

Colposcopy. Obstet Gynecol 2012

Exicisional techniques of treating CIN

LEEP (loop electrosurgical excisional procedure)

Loop electrosurgical excision procedure (LEEP) was first demonstrated by Walter Prendiville in 1986.The majority of patients can be treated under local anesthesia asoutpatients, and the excised tissue can be sent for histopathologicevaluation. The length of the excised cervical cone depends on the type oftransformation zone.Properly performed LEEP causes only minimal thermonecrosis on thesurgical resection margin.

Kyrgiou M, et al. Fertility and early pregnancy outcomes after treatment for

cervical intraepithelial neoplasia: systematic review and meta-analysis. BMJ 2014

Arbyn M, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: metaanalysis.BMJ 2008

Treatment success of LEEP is reported as 91- 98% in non-randomised studies.

Complications have been reported in 7-10% of treated women.

50-70% of these complications are intra or post-operative bleeding. Haemostasis can be achievedeasily by application of Monsell’s solution.

Other complications are purulent vaginal discharge and pelvic pain.

The risk of cervical incompetence is dependent on the depth of the stromal tissue removed during the procedure.

Cervical stenosis is reported in a small number of cases which may lead to hematometria, infertility and difficulties during subsequent colposcopy.

Loop Electrosurgical Excisional Procedure(LEEP)

Murdoch 1992, Prendeville 1989

Cold knife conization (CKC)

Cervical conization with a scalpel is an excisional method generally reserved for treating

adenocarcinoma in situ and microinvasive carcinoma.

CKC avoids the thermal artifact of LEEP and Laser, thus allowing better histopathological

assessment of cone margins.

The major disadvantages of CKC are that the procedure has to be performed under

regional or general anesthesia for which hospitalization will be necessary and

complications such as primary and secondary hemorrhage and adverse pregnancy events

are higher than LEEP.

Martin-Hirsch PP et al. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev 2013

Laser conization

This procedure can be performed under general or local analgesia.

A highly focused laser spot is used to make an ectocervical circumferential incision

to a depth of 1 cm.

The major advantages are accurate tailoring of the size of the cone, low blood loss

in most cases, and less cervical trauma than with knife cut cones.

Disadvantage of laser conization is that the cone biopsy specimen might suffer from

thermal damage, making histological evaluation of margins impossible.

The treatment success of laser cone biopsy is reported as 93% to 96% in non-randomisedstudies.

Bostofte 1986, Tabor 1990

Cochrane Database Syst Rev. 2010

Surgery for cervical intraepithelial neoplasia.

Martin-Hirsch PP

Cochrane Database Syst Rev. 2010

Surgery for cervical intraepithelial neoplasia.

Martin-Hirsch PP

2018

In this randomized trial, they demonstrated that LEEP-DCV leads to significantly smaller cone specimenswithout compromising margin status.

The risk of residuel or recurrent CIN2+ lesionsare increased with positive compared withnegative resection margins.High-risk HPV DNA testing post-treatment, more sensitive and similarly specific compared with the margin status.

Incomplete Excision of Cervical Intraepithelial Neoplasia as a Predictor of the Risk of Recurrent Disease – a 16 Year Follow-Up Study

Susanna Alder, David Megyessi, Karin Sundström

Objectives: In this study, we examine the long-term risk of residual/recurrent CIN2+ among women previously treated for CIN2 or 3 and how this varies according to margin status (considering also location), as well as comorbidity (conditions assumed to interact with hrHPV acquisition and/or CIN progression), post-treatment presence of hrHPV and other factors.

Study Design: This prospective study included 991 women with histopathologically-confirmed CIN2/3 who underwent conization in 2000-2007. Information on the primary histopathologic finding, treatment modality, comorbidity, age and hrHPV status during follow-up and residual/recurrent CIN2+ was obtained from the Swedish National Cervical Screening Registry and medical records. Cumulative incidence of residual/recurrent CIN2+ was plotted on Kaplan–Meier curves, with determinants assessed by Cox regression.

Results: During a median of 10 years and maximum of 16 years follow-up, 111 patients were diagnosed with residual/recurrent CIN2+.

Women with positive/uncertain margins had a higher risk of residual/recurrent CIN2+ than women with negative margins, adjusting for potential confounders (hazard ratio (HR)=2.67; 95% confidence interval (CI): 1.81–3.93).

The risk of residual/recurrent CIN2+ varied by anatomical localization of the margins (endocervical: HR=2.72; 95%CI: 1.67–4.41) and both endo- and ectocervical(HR=4.98; 95%CI: 2.85-8.71).

The risk did not increase significantly when only ectocervical margins were positive/uncertain.

The presence of comorbidity (autoimmune disease, human immunodeficiency viral infection, hepatitis B and/or C, malignancy, diabetes, genetic disorder and/or organ transplant) was also a significant independent predictor of residual/recurrent CIN2+.

In women with positive hrHPV findings during follow-up, the HR of positive/uncertain margins for recurrent/residual CIN2+ increased significantly compared to women with hrHPV positive findings but negative margins.

Conclusions: Patients with incompletely excised CIN2/3 are at increased risk of residual/recurrent CIN2+.

Margin status combined with hrHPV results and consideration of comorbidity may increase the accuracy for predicting treatment failure.

Margin status combined with hrHPV results may increase the accuracy for predicting treatment failure.

More than 15 mm

Pregnancy outcomes

Take home messages

CIN1 lesions usually do not require any treatment unless the lesion is persistent beyond two years.

CIN2 lesions over-expressing p16INK4 need treatment while those negative on these tests can be followed up.

There is international consensus that CIN3 lesions should be treated following diagnosis, except in pregnancy.

The obstetrical morbidity related to CIN excisional treatment depends on the dimensions of the removed cervical tissue.

The risk of premature delivery following excision appears to be significant in women whose depth of excised cone is greater than 10 mm.

Excisional treatment should be used only in well-selected women with a clear indication and should be

guided by colposcopy.

Margin status also appears to be of crucial importance, positive margin exposes patient to a substantial risk of high grade post-treatment disease.

Colposcopy would allow for the optimization of excisional procedures both in terms of margin status and excised cone dimensions.

Margin status combined with hrHPV results may increase the accuracy for predicting residuel/recurrent lesions.

Cold knife conisation should be reserved for treating adenocarcinoma in situ and microinvasive carcinoma.

LEEP should be the first line procedure in women with fertility concerns.

Take home messages